Atherothrombosis is a major cause of morbidity and mortality in patients with type 2 diabetes (T2DM). Although[unreadable] some of the causes responsible for this finding have been determined (e.g. hypertension, smoking, dyslipidemia)[unreadable] many of other putative mechanisms remain ill-defined. Remarkably, limited specific information exists identifying[unreadable] which of the parameters present in the disordered metabolic milieu occurring in T2DM are mechanisms responsible[unreadable] for the increased prothrombotic state and reduced endothelial function characteristic of this condition. The studies[unreadable] outlined in this proposal are focused on determining the in-vivo "metabolic" mechanisms causing the increased[unreadable] prothrombotic state that occurs in T2DM. Studies will determine whether it is insulin, hyperglycemia or insulin[unreadable] resistance that is a mechanism for disordered fibrinolytic balance and decreased endothelial function in T2DM.[unreadable] Additionally, studies aimed at determining the effects of high glucose, high FFA and basal insulin on fibrinolytic[unreadable] balance will also be proposed. We will introduce a new, clinically relevant area of research by determining the[unreadable] effects of hypoglycemia on endothelial function and vascular fibrinolytic balance in T2DM. Experiments will use the[unreadable] glucose clamp and pituitary-pancreatic-glucose clamp techniques, to precisely control glycemic and endocrine[unreadable] environments during our studies. Endothelial and non-endothelial dependent function will be determined by graded[unreadable] intra-arterial infusions of bradykinin and sodium nitroprusside. Vascular fibrinolytic balance will be determined by[unreadable] measuring plasma PAI-1 and arterial t-PA release. The specific aims of this proposal are to determine: 1) To[unreadable] determine the effects of hyperglycemia per se and hyperinsulinemia per se on disordered fibrinolytic balance and[unreadable] endothelial dysfunction in patients with diabetes, 2) To determine the effects of elevated free fatty acids and[unreadable] hyperglycemia on endothelial function and fibrinolytic balance in patients with type 2 diabetes, 3) To determine the[unreadable] effects of hypoglycemia on fibrinolytic balance in patients with diabetes, and 4) To determine the roles played by[unreadable] corticosteroid receptors on hypoglycemia effects on vascular fibrinolytic balance and endothelial function in patients[unreadable] with type 2 diabetes.